Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that bind to fatty acids such as oleic acids which are important metabolic fuels and cellular regulators. Dysregulation of fatty acid metabolism in adipose tissue is a prominent feature of insulin resistance and the transition from obesity to non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes).
aP2 (adipocyte fatty binding protein), an abundant 14.6 KDa cytosolic protein in adipocytes, and one of a family of homologous intracellular fatty acid binding proteins (FABPs), is involved in the regulation of fatty acid trafficking in adipocytes and mediates fatty acid fluxes in adipose tissue. G. S. Hotamisligil et al, “Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein”, Science, Vol. 274, Nov. 22, 1996, pp. 1377-1379, report that aP2-deficient mice placed on a high fat diet for several weeks developed dietary obesity, but, unlike control-mice on a similar diet, did not develop insulin resistance or diabetes. Hotamisligil et al conclude “aP2 is central to the pathway that links obesity to insulin resistance” (Abstract, page 1377).
Also, it has been shown by Uysal et al in “Improved glocose and lipid metabolism in genetically obese mice lacking aP2” in Endocrinology, Vol. 141, 2000, pp. 3388-3396 that ob/ob mice deficient of aP2 had lower plasma glucose, improved peripheral insulin resistance, and beneficial effects on lipid metabolism.
Additionally, Makowski et. al. in “Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis” in Nature Medicine, Vol. 7, 2001, pp. 699-705 showed that Apoe−/− mice with either total aP2 deficiency or aP2−/− macrophage deficiency showed reductions in the formation of atherosclerotic plague, as well as reduction of TNF-alpha and a variety of inflammatory cytokines, as compared to aP2 replete ApoE−/− mice.
Since it is known that both aP2 and k-FABP (mal-1), both intracellular fatty acid binding proteins, are expressed in both adipocyte and macrophage cells, concommitant inhibition of both FABPs should be expected to have greater effects in treating the diseases such as diabetes, obesity, atherosclerosis, inflammation, and those previously mentioned.
PCT applications WO 00/15229 and WO 00/59506 disclose methods for treating diabetes employing an aP2 inhibitor.